Method of Reducing the Toxicity of Anticancer Agents

U.S. Patent Number: 6,939,893
Date Issued: September 6, 2005

Summary: The invention discloses a method for enhancing the efficacy of anti-cancer agents. The method comprises administering to an individual, in need of such a treatment, an anticancer agent and a selenium compound. The selenium compounds may be administered before, during or after administration of the anti-cancer agent.

Detail: In the invention it was observed that administration of selenium compounds reduces the toxicity of anticancer agents. Data is presented for in vivo studies in two animal models. The invention discloses a method for reducing the toxicity of anticancer agents. The method comprises administering to an individual, in need of treatment, an anti-tumor agent and a selenium compound. The selenium compounds may be administered before, during or after administration of the anti-cancer agent. In one embodiment, the selenium compound is administered prior to chemotherapy and may be continued during and after the chemotherapy.

Combination Therapy of Mononmethylated Selenium Compounds and Anti-Steroid Hormone Agents

U.S. Patent: Pending
Application Number: 11/146,363

Summary: This invention relates to the use of selenium compounds in combinations with anti-hormone compounds and the use of such a combination to treat various hormone-dependent cancers including cancers of the prostate, breast, ovaries and endometrium, as well as non-malignant conditions such as uterine fibroids, endometriosis and prostate hyperplasia.

5-Amino-4-Imidazolecarboxamide Riboside as Potentiator of Antifolate Transport and Metabolism

U.S. Patent: Pending
Application Number: 11/327,872

Summary: The invention provides a method for increasing the efficacy of antifolates which act via inhibition of dihydrofolate reductase (DHFR). The method comprises the steps of administration of 5-amino-4-imidazolecarboxamide riboside (Z) or its base with the antifolate such that the targeted cells are exposed to both the antifolate and Z simultaneously. This results in increased influx of the antifolate. For MTX, accumulation of the more biologically active polyglutamate forms is also potentiated. This potentiation appears to be mediated by an effect on the RFC.

Detail: The invention provides a method for enhancing the uptake and efficacy of antifolates which act via inhibition of DHFR such as the 2,4 diaminopteridine antifolates methotrexate and aminopterin.The method is based on the unexpected observation that exogenous 5-amino-4-imidazolecarboxamide riboside (Z), a nucleoside precursor of (among others) the triphosphate ZTP, potentiates uptake of MTX and synthesis of MTX polyglutamate in cancer cells. Based on the data presented herein, it is considered that Z potentiates transport of antifolates via the RFC and the increased transport leads to increased synthesis of antifolate polyglutamates and consequently increased drug accumulation. Z was observed to enhance the growth inhibitory potency of MTX against cancer cells.Thus in one embodiment, this invention provides a method comprising the administration of Z or its base (i.e., 5-amino-4-imidazolecarboxamide) with an antifolate which acts via inhibition of the DHFR at concentrations at which the antifolate inhibits DHFR. The administration of Z or its base can be accomplished by any standard method, although systemic administration is preferred. Z has already been tested in clinical trials as a treatment for cardiac ischemia and is known to be nontoxic.In another embodiment, Z or its base and an antifolate which acts via inhibition of DHFR can be administered with a second antifolate(s) which primarily act via another mechanism such as inhibition of thymidylate synthase, inhibition of purine synthesis or other multi-targeted inhibition pathways. Administration of Z or its base with folate(s) which inhibit DHFR (with or without other folates) to enhance the efficacy of the folate(s) can be carried out for inhibiting the growth of cells as in various cancers as well as in other pathological conditions such as rheumatoid arthritis and psoriasis.

Method of Augmenting the Antitumor Activity of Anticancer Agents

U.S. Patent: Pending
Application Number: 11/405,377

Summary: A method for augmenting the antitumor activity of anti-cancer agents is provided. The method comprises administering to an individual an anti-cancer and a selenium compound. A method is also provided for inhibiting the growth of a tumor which-has proven to be refractory to anticancer agents. The methods comprises administration of selenium compound followed by administration of the anticancer agent.

Detail: It was observed that administration of selenium compounds augments the antitumor activity of anticancer agents. Data is presented for in vivo studies in xenograft bearing animals. Additionally, clinical studies have been carried out which further confirm augmentation of antitumor activity of anticancer agents by administration of selenium. While tumor shrinkage was observed for several chemotherapeutic agents, the effect was not durable with all chemotherapeutic agents and complete tumor regression (cure) was observed only with irinotecan and taxotere. Further, it was observed that the augmentation of activity was provided by the administration of seleno-L-methionine (SLM) and methylseleno cysteine (MSC), but not sodium selenite (SS) or methylseleninic acid (MSA). The selenium compound is preferably administered at least three days prior to the administration of the antitumor agent. Accordingly, the present invention discloses a method for augmenting the antitumor activity of anticancer agents selected from the group consisting of irinotecan and taxotere. The method comprises administering to an individual having a tumor, the anti-tumor agent and a selenium compound selected from the group consisting of SLM and MSC. In one embodiment, the selenium compound is administered at least 3 days prior to chemotherapy and may be continued during and after the chemotherapy.

Vitamin D Polymorphisms and Splice Variants in Metabolizing Enzymes as Markers for Vitamin D Exposure and Associated Diseases

U.S. Patent: Pending
ApplicationNumber: 11/700,462

Summary: A method is provided for identifying an individual as having altered vitamin D metabolism comprising analyzing a biological sample from the individual for the presence of CYP24 SNPs and/or aberrantly spliced CYP24 mRNA. The presence of the SNPs and/or the aberrantly spliced CYP24 mRNA indicates that the individual has altered vitamin D metabolism. Also provided are methods for customizing dosages of biologically active vitamin D compounds for individuals who are determined to have altered vitamin D metabolism.

Detail: The invention provides a method for identifying an individual as likely having altered vitamin D metabolism. The method comprises obtaining a biological sample from the individual and determining the presence of certain CYP24 single nucleotide polymorphisms (SNPs) and/or aberrantly spliced CYP24 mRNA, and/or correctly spliced CYP24 mRNA in the absence of calcitriol, wherein the presence of the SNPs and/or aberrantly spliced CYP24 and/or correctly spliced CYP24 mRNA in the absence of calcitriol is indicative that the individual is likely to have altered vitamin D metabolism. Also provided is a method for customizing dosing of calcitriol or calcitriol precursors, or a vitamin D analog compound that does not generate as much of a calcemic response as calcitriol. The method comprises obtaining a biological sample from the individual, identifying the presence of CYP24 SNPs and/or aberrantly spliced CYP24 mRNA and/or correctly spliced CYP24 mRNA in the absence of calcitriol, and based upon such identification, prescribing a lower or higher dose of calcitriol or calcitriol precursors.